Quinolyl oxamic acids

ABSTRACT

A compound of the formula   WHEREIN M is selected from the group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation, X is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive; alkoxy from one to three carbon atoms, inclusive; halogen, and trifluoromethyl with the proviso that when X is hydrogen, the   GROUPING IS LIMITED TO THE 6 POSITION; AND PHARMACEUTICAL COMPOSITIONS THEREOF, IN THE PROPHYLACTIC TREATMENT OF SENSITIZED HUMANS AND ANIMALS FOR ALLERGY AND ALL ANAPHYLACTIC REACTIONS OF A REAGIN OR NON-REAGIN MEDIATED NATURE.

United States Patent 1191 Wright [451 May 27, 1975 1 QUINOLYL OXAMICACIDS [75] Inventor: John B. Wright, Kalamazoo, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

22 Filed: Dec. 20, 1972 211 App]. No.: 316,977

OTHER PUBLICATIONS Teitz, Clinical Chemistry, 1971, pp. 383, 850.

Primary Examiner--Donald G. Daus Assistant Examiner-David E. WheelerAttorney, Agent, or Firm-Martin B. Barancik; Roman Saliwanchik [57]ABSTRACT A compound of the formula wherein M is selected from the: groupconsisting of hydrogen and a pharmaceutically acceptable metal or aminecation,

X is selected from the group consisting of hydrogen, alkyl from one tothree carbon atoms, inclusive; alkoxy from one to three carbon atoms,inclusive; halogen, and trifluoromethyl with the proviso that when X ishydrogen, the

grouping is limited to the 6 position; and pharmaceutical compositionsthereof, in the prophylactic treatment of sensitized humans and animalsfor allergy and all anaphylactic reactions of a reagin or non-reaginmediated nature.

, 10 Claims, No Drawings QUINOLYL OXAMIC ACIDS BRIEF SUMMARY OF THEINVENTION It has been discovered that novel compounds of Formula la areuseful in the prophylactic treatment of sensitized humans and animalsfor allergy and all anaphylactic reactions of a reagin or non-reaginmediated nature. The compounds are formulated with pharmaceuticalcarriers for oral, parenteral, rectal or inhalation means ofadministration.

DETAILED DESCRIPTION OF THE INVENTION In accordance with this inventionare provided compounds represented by structure Ia:

wherein it is understood that Ia can exist in its tautomeric form Ib andthat the compounds of this invention are likely to be mixtures of alltautomeric forms, the percentages of each tautomer to be at leastpartially dependent on the nature of M and X, and the physicalenvironrnent of the compound.

grouping is limited to the 6 position.

The preferred compounds are those compounds where M is an amine cation,X is selected from the group consisting of alkyl of from one to threecarbon atoms, inclusive; and halogen and the grouping is at the 7position.

The most preferred M group is the cation oftris(hydroxymethyl)aminomethane. I

As employed in the above disclosure and throughout the specification,the term halogen includes fluoro, chloro, bromo, and iodo and the termalkyl includes methyl, ethyl, propyl, and isopropyl when limited to 3carbon atoms. A pharmaceutically acceptable metal or amine cationincludes alkali metals such as sodium and potassium, alkaline earthmetals such as magnesium and calcium, other acceptable metals such asaluminum and amine cations. The term amine cations includes allpharmaceutically acceptable amine cations of the invention, includingfor example, cations of the amine ammonia,tris(hydroxymethyl)aminomethane, D-threo-Z-aminol -p-nitrophenyll ,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyll-propanol, 2-amino-2-methyl-l ,3- propanediol and2,2'-bis(liydroxymethyl)-2,2,2"- nitriloethanol and further aminesincluding H NR, I'INR' and NR':, wherein R'is selected from the groupconsisting of alkyl from one to three carbon atoms, inclusive, and -CI-ICI-I OI-I.

The compounds of this invention can be prepared by methods known to theart. The basic synthetic pathway employed is the reaction of anappropriately substituted nitroaniline (1) with an oxaloacetate sodiumsalt or acetylene dicarboxylate (111) in the presence of a solvent toform the adduct (111). The R group of reagent (11) is limited to alkyloffrorn one to three carbon atoms, inclusive; and phenyl. Ring closureto the 1,4- dihydronitro-8-substituted-4-oxoquinaldate (1V) isaccomplished by heating the adduct at appropriate conditionsl (IV) isthen reduced to the amino compound (V) under standard reducingconditions. Compound (V) is then reacted with ethyl oxalyl chloride in asolvent and base under suitable conditions to form ethyl (2-carboalkoxyl ,4-dihydro-8-substituted 4- oxoquinolyl)oxamate (VI), orits 2-carbophenoxy analog, which is then treated with sodium hydroxideto form the acid (VII).

O H 11 H l I 0 0 H n n HO-C-C-N I .fter the above synthesis has beencarried out, the aoxy acid is converted to the metal or amine salts byldard methods.

-Substituted-nitroaniline starting materials are wn to the art. Includedamong starting materials 1e available in the art are the followingtwostituted nitroaniline compounds where nitro is deslted at either the3,4, or 5 position.

TABLE I Ring Position In the formation of the adduct, subsequent ringclosure and succeeding reactions in the synthetic pathway,

the following processing conditions and reagents can be employed.

When using the oxaloacetate reagent to form the adduct, there should bea sufficient amount of acid present to protonate the oxaloacetatecarbanion and catalyze the removal of the keto grouping. The acid canalso serve as a solvent for the two reagents as well. For example,glacial acetic acid, propionic acid, p-toluene sulfonic acid, andbutyric acid are acids which can, be used. If a further reagent isneeded to place the two reactants into solution (or a cosolventdesired), benzene, toluene, diethylether, dioxane, tetrahydrofuran, oralcohols from one to about four carbon atoms can be employed. The lengthof time for the formation of the adduct is temperature dependent. Atroom temperature the reaction proceeds rather slowly but as thetemperature is raised, reaction time is decreased. Acceptable reactiontimes are achieved at temperatures ranging from about 40 to about C.,although reaction temperatures can be above C., if desired.

With regard to the use of the acetylene dicarboxylate reactant in theformation of the adduct, appropriate solvents are alcohols having fromone to about six carbon atoms, preferably one to about three carbonatoms, benzene, diethylether, dioxane, tetrahydrofuran, or any othersolvent which places both of the reactants in solution and allows thedesired compound to form. Generally the reaction proceeds readily atroom temperature and can be promoted by an increase in temperature toabout 100C.

Ring closure of the adduct, prepared by the methods disclosed above, andformation of the quinoline ring can be accomplished by heating theadduct at a relatively high temperature. This heating can be done to theneat adduct. However, it is preferred to use a solvent which canfunction as a heat transfer medium. Any high boiling inert solvent suchas a mineral oil, hexamethylphosphoric triamide, diphenylether, orDowtherm A, which appears to be primarily diphenylether, is suitable.The ring cyclization step is preferably carried out at temperatures offrom about 220C. to about 280C, although lower or higher temperaturescan be employed if desired. Particularly preferred solvents are DowthermA, or diphenylether, which boil at about 250C., thus enabling the ring Icyclization to occur during reflux.

An additional advantage of the elevated temperature during the ringcyclization is that any adduct formed in the preceding step which is notin a position to cyclize since it is trans to the benzene ring isisomerized to the cis configuration during the heating, thereby allowingsubstantial yields of the desired compound to be produced. This transadduct preparation occurs more frequently when an aprotic solvent andacetylene dicarboxylate are used in the adduct formation step.

The nitro grouping of the nitro l,4-dihydro-8-substituted-4-oxoquinaldate formed in the ring closure step is reducedto amino. This reduction can be conveniently effected by catalytic meanssuch as Raney Nickel or palladium or charcoal or platinum in thepresence of hydrogen. Additionally, chemical means quinolyloxamic acidby using dilute base such as sodium hydroxide, potassium hydroxide orpotassium carbonate at temperatures ranging from about 25C. to about100C. The acid can then be easily converted to the metal or amine saltby contacting the diacid with two equivalents of the desiredmetalhydroxide or amine and heating in a sufficient amount of water toeffect solubilization. The crystalline salts can be precipitated by theaddition of methanol.

Following is an illustrative list of compounds of the invention whichcan be prepared by the above disclosed procedures. Intended to beincluded are compounds made from the starting materials of Table l.

Where M is Hydrogen Ring Position of 0 -t 1'E-E0M 22 a iC3H7 5 oc 'n. r

[MC- H, 6

(Ll J l 7 cr TABLE III i the same manner as Table II, but the sameillustrative scoping is intended.

The following examples are compounds in accordance with this invention.The compounds are intended not to limit but merely to exemplify theinvention.

EXAMPLE 1 (2-Carboxy-l ,4-dihydro- 8-methyl-4-oxo- 7-quinolyl)oxamicacid a. Dimethyl (3-nitro-o-toluidino)butenedioate A suspension of 49.6grams (0.325 mole) of 2-methyl-3-nitroaniline in 500 ml. of methanol isstirred at room temperature, and 46.15 grams (0.325 mole) of dimethylacetylenedicarboxylate is added dropwise. The solution .stands at roomtemperature for 18 hours. As the reaction proceeds, a precipitate forms.The precipitate is removed by filtration and recrystallized fromethanol-water. The yellow needles melt at 99100C.

Anal. Calcd. for: G i-M09 0 C, 53.24; H, 4.47; N, 9.55; Found: C, 53.11;H, 4.77; N, 9.31.

The infrared spectra is in agreement. The NMR spectra indicates a 60/40mixture of cis and trans isomers.

b. Methyl 7-aminol ,4-dihydro-8-methyl-4-oxoquinaldate A solution of29.3 grams (0.1 mole) of dimethyl (3- nitro-o-toluidino)butenedioate in200 ml. of refluxing Dowtherm. The reaction mixture is refluxed for 15minutes and cooled to room temperature. The product is removed byfiltration and recrystallized from dimethylformamide-ethanol to giveyellow needles melting at 135.

A suspension of 10.44 grams (0.04 mole) of the above compound in 180 ml.of dimethylformamide and 1 gram of 10% palladium on. charcoal ishydrogenated on a Parr apparatus. The theoretical amount of hydrogen istaken up in 15 minutes. The catalyst is removed by filtration and thesolvent removed by distillation in vacuo. The residue is recrystallizedfrom ethanol-water to yield yellow crystals melting at 238 (dec.).

c. Product To a solution of 6.97 grams (0.03 mole) of methyl 7-amino-8-methyll ,4-dihydro-4-oxoquinaldate, in l ml. of drydimethylformamide is added 3.06 grams of triethylamine. The resultingsolution is cooled to 0C and there is added, dropwise., 4.10 grams ofethyl oxalyl chloride, keeping the temperature below 5. The mixture isthen stirred at 0for 2 hours and allowed to stand overnight. Thedimethylformamide is removed by distillation under reduced pressure.Water is added, the mixture stirred, and the solid removed byfiltration. The resulting solid is dissolved in methylene chloride andthe resulting solution extracted with a 5% sodium hydroxide solution.The mixture is shaken for 15 minutes. The agueous layer is separated,acidified by the addition of dilute hydrochloric acid, and'theprecipitate removed by filtration and washed with water. The material ispurified by dissolving it in dilute Nal-lCO solution, filtering thesolution, reacidifying the filtrate by the addition of a filteredsolution of dilute hydrochloric acid, removing the precipitate byfiltration and washing the precipitate with hot water and then hotethanol. There is obtained 1.66 gram of a tan solid melting at 275(dec.).

Anal. Calcd. for: C I-1 N 0 N, 9.65. Found: N, 9.21

Example 2 (2-Carboxy-1,4-dihydro-4-oxo-6quinolyl)oxamic acid a. Methyl6-amino-l ,4-dihydro-4-oxoquinaldate A suspension of 9.92 grams (0.04mole) of methyl 6-nitro-1,4-dihydro-4-oxoquinaldate and 180 ml. ofdimethylformamide with 1 gram of 10% palladium on charcoal ishydrogenated on a Parr apparatus at 50 pounds of pressure. After 15minutes the theoretical amount of hydrogen has been absorbed. Thecatalyst is removed by filtration. The filtrate is evaporated toonethird the original volume and poured into 1500 ml. of water. Theresulting green needles are filtered off to yield 8.70 grams (100%) ofmaterial melting at 230 (dec.). The needles are boiled in ethanol andfiltered, increasing the melting point to 235 (dec.).

Anal. Calcd. for: C H N O C, 60.54; H, 4.62; N, 12.84. Found: C, 60.38;H, 4.69; N, l2.65.

The infrared and NMR spectra are in agreement.

b. Ethyl (2-carbomethoxy-1,4-dihydro- 4-oxo-6-quinolyl)oxamate Asolution of 3.26 grams (0.02 mole) of methyl 6- amino-l,4,dihydro-4-oxoquinaldate in 100 ml. of dimethylformamide is stirredand cooled to in an ice bath. To the cold solution is added 2.05 gramsof triethylamine and, dropwise, 2.73 grams of ethyl oxalyl chloridewhile the temperature of the solution is maintained at 0C. The reactionmixture is stirred for 2 hours in the ice bath, then warmed to roomtemperature and stands for 48 hours. The resulting yellow precipitate isfiltered off and washed with ethyl acetate. The yellow solid is boiledin hot ethanol and filtered to give 4.74 grams (74%) of material meltingat 295 (dec.).

Anal. Calcd. for: C H N O C, 56.60; H, 4.43; N, 8.80. Found: C, 56.13;H, 4.50; N, 8.84.

The infrared and NMR spectra are in agreement.

0. Product A solution of 3.64 grams (0.0114 mole) of ethyl (2carbomethoxy-l ,4-dihydro-4 oxo-6-quinolyl)-oxamate in 100 ml. ofmethylene chloride is shaken well with 74 ml. of a sodium hydroxidesolution for minutes. The aqueous phase is separated and acidified withdilute hydrochloric acid. The precipitate is removed by filtration,washed with water and then with ethanol. The product is purified bydissolving it in a 1% sodium hydroxide solution, filtering, andreacidifying the filtrate with a filtered solution of dilutehydrochloric acid. There is obtained 1.57 gram of a tan solid melting at305 (dec.).

Example 3 (2-Carboxy-l ,4-dihydro-8-methyl-4-oxo-5- quinolyl)oxamic acida. Methyl l,4,dihydro-8-methyl-4-oxo-5-nitroquinaldate To a stirredsolution of 30.43 grams (0.2 mole) of 2-methyl-5-nitroaniline in 500 ml.of methanol is added 28.5 grams (0.02 mole) of dimethylacetylenedicarboxylate. A yellow precipitate forms within minutes. Thereaction mixture is allowed to stand at room temperature for 18 hours.There is obtained 48.5 grams (33%) of yellow needles melting at 129-13l.

Anal. Calcd. for: C,,,H,,N,o,,.

C, 53.24; H, 4.47; N, 9.55. C, 53.65; 'H. 4.83; N, 9.56. The infraredspectra is in agreement. 5 the NMR spectra indicated a mixture of cisand trans isomers.

Found:

To 150 ml. of refluxing Dowtherm A is added 22.3 grams (0.75 mole) ofthe above sample. Refluxing is continued for 30 minutes. The solution iscooled to room temperature. The resulting tan needles are filtered offand washed with Skellysolve B. There is obtained 14.00 grams (72%) oftan needles melting at 215-216.

Anal. Calcd. for: C H N O C, 54.96; H, 3.84; N, 10.68.

Found: C, 55.09; H, 4.l2; N, 10.46.

The infrared and NMR spectra are in agreement.

g b. Methyl S-amino- 1 ,4-dihydro-8-methyl-4-oxoquinaldate Anal. Calcd.for: C, H, N O

C, 62.06; H, 5.21; N, 12.06. Found: C, 61.85; H, 5.21; N, 12.02.

The infrared and NMR spectra are in 40 agreement.

c. Ethyl (2-carbomethoxy-1,4-dihydro-8-methyl-4-oxo-5- 5 quinolyl)oxamate To a stirred solution of 17.5 grams (0.075 mole) of methylS-amino- 1 ,4-dihydr0-8-methyl-4-oxoquinaldate in 350 ml. ofdimethylformamide at 0C. is added 7.7 grams of triethylamine anddropwise, at 5C. 10.4 5 grams of ethyl oxalyl chloride. The mixture isstirred at 5C. for 2 hours and then allowed to stand overnight. Theprecipitate is removed by filtration and recrystallized fromdimethylformamide to give yellow needles melting at 250-252".

Anal. Calcd. for: C ,H, =,N O,;.

C, 57.83; H, 4.85; N, 8.94. Found: C, 58.17. H. 4. 9; N, .51.

d. Product A mixture of 4.39 grams (0.0132 mole) of ethyl (2-carbomethoxy-l ,4-dihydro-8-methyl-4-oxo-5- quinolyl)oxamate, 100 ml. ofmethylene chloride, and

65 ml. of 5% sodium hydroxide solution is shaken for 10 minutes in aseparatory funnel. The aqueous layer is separated and acidified by theaddition of a dilute hydrochloric acid solution. The yellow precipitateis removed by filtration. There is obtained 3.70 grams of materialmelting at 275 (dec.).

Anal. Calcd. for: C H N O N, 9.65. Found: N, 9.64.

EXAMPLE 4 2-Carboxy1,4-dihydro-8-methyl-4-oxo-6- quinolyl )oxamic acidAnal. Calcd. for: C H N O C, 53.06; H, 4.80; N, 9.52. Found: C, 53.00;H, 4.79; N, 9.54.

To 500 ml. of refluxing Dowtherm is added 56 grams (0.19 mole) of thematerial obtained above. The mixture is heated under reflux for 10minutes and allowed to cool. The r sulting precipitate is removed byfiltration. There is obtained 39.7 grams (80%) of yellow-tan needlesmelting at 222 (dec.). Recrystallization from dimethylformamide givesmaterial melting at 270 (dec.).

Anal. Calcd. for: C H N O C, 54.96; H, 3.84; N, 10.68. Found: C, 54.61;H, 3.93; N, 11.00.

The infrared and NMR spectra are in agreement.

b. Methyl 6-amino-1,4-dihydro-8-methyl-4-oxoquinaldate A suspension of5.24 grams (0.02 mole) of methyl1,4-dihydro-8-methyl-6-nitro-4-oxoquinaldate and 1 gram of 10%palladium-on-charcoal catalyst, and 40 ml. of dimethylformamide ishydrogenated at an initial pressure of 3 atmospheres. The catalyst isremoved by filtration and the filtrate is poured into 500 ml. of water.The precipitate is removed by filtration and recrystallized frommethanol. There is obtained 2.72 grams of yellow prisms melting at 236(dec.).

Anal. Calcd. for: C, H, N O;,.

C, 62.06; H, 5.21; N. 12.06. Found: C, 61.54; H, 5.38; N, 12.04.

The infrared and NMR spectra are in agreement.

c. Ethyl (2-carbomethoxyl ,4-dihydro-8-methyl-4-oxo-6- quinolyl )oxamateUtilizing the procedure described above for ethyl 2- carboxymethoxy-l ,4dihydro--8-methyl-4-oxo-5- quinolyl)oxamate with an equivalent amount ofmethyl 6-aminol ,4-dihydro-8-methyl-4-oxoquinaldate, there is obtainedethyl (Z-carbomethoxy-l ,4-dihydro-8- l0 methyl4-oxo-6-quinolyl)oxamate.

d. Product Hydrolysis of the diester above with sodium hydroxidesolution according to the procedure described above for(2-carboxyl1,4-dihydro-8-methyl-4-oxo-5- quinolyl)oxamic acid gives(2-carboxy-1,4-dihydro-8- methyl-4-oxo-6-quinolyl)oxamic acid.

EXAMPLE 5 (2-Carboxy-8-chloro l ,4-dihydro-4-oxo-5 quinolyl)oxamic acida. Methyl 8-chloro-1,4-dihydro-5-nitro-4-oxo-quinaldate A mixture of29.0 grams (0.164 mole) of 2-chloro-5- nitroaniline, 150 ml. of methanoland 25.4 grams (0.164 mole) of dimethyl acetylenedicarboxylate is heatedunder reflux for 6 hours and allowed to stand overnight. The precipitateis removed by filtration.

There is obtained 41.0 grams (89%) of yellow needles melting at l57-158.Recrystallization from methanol does not raise the melting point.

Anal. Calcd. for: C H ClN O,

C, 45.80; H, 3.52; Cl, 11.27; N, 8.90 Found: C, 45.75; H, 3.51; Cl,11.44; N, 8.98

To 300 ml. of refluxing Dowtherm is added 29.4

grams (0.094 mole) of the product obtained above. The mixture is heatedunder reflux for 1 hour, allowed to cool, the precipitate is removed byfiltration. There is obtained 21.6 grams of yellow needles melting at196-200. A sample is purified by boiling with methanol and filtering.The product obtained melts at 197-198.

Anal. Calcd. for: C H-,ClN O C, 46.74; H, 2.49; Cl, 12.5 N, 9.9 5

5 1 Found: C, 46.47; H, 2.50; Cl. 12.64; 9. 9

b. Methyl 5-amino-8-chlorol ,4-dihydro-4-oxoquinaldate A mixture of 6.06grams (0.0214 mole) of methyl 8-chloro-1,4-dihydro-5-nitro-4-oxoquinaldate in ml. of methanol and 6grams of Raney Nickel is hydrogenated on a Parr apparatus under 3atmospheres of pressure for 1 hour. The catalyst is removed byfiltration 65 and the solvent removed by distillation in vacuo, to

yield 290 grams melting at l65-173. Recrystallization from methanolyields 2.45 grams of red needles melting at -176.

Anal. Calcd. for: C H CIN Q,

C. 52.29; H, 3.59; Cl, 14.02; N, 11.09 Found: C, 51.96; H. 3.53; Cl,13.51; N. 11.11 The infrared and NMR spectra are in agreement.

0. Product Treatment of methyl 5-amino-8-chloro-l,4-dihydro-4-oxoquinaldate with ethyl oxalyl chloride in the presence oftriethylamine followed by saponification of the resulting diesteraccording to the procedure described above for(2-carboxy-l,4-dihydro-8-methyl-4-oxo-7- quinolyl)oxamic acid gives(2-carboxy-8-chloro-1,4- dihydro-4-oxo-5-quinolyl)oxamic acid.

EXAMPLE 6 (2-Carboxy-8-chloro-1,4-dihydro-4-oxo-6- quinolyl)oxamic acida. Methyl 8-chloro-l ,4-dihydro-6-nitro-4-oxoquinaldate To a solution of70.8 grams (0.4 mole) of 2-chloro-4- nitroaniline in 300 ml. of methanolis added with stirring 56.8 grams of dimethyl acetylenedicarboxylate.The solution is heated under reflux for 6 hours and allowed to cool. Theyellow needles removed by filtration melt at l42-l48.

Twelve and one-half grams of the above product are placed in 150 ml. ofrefluxing Dowtherm and the mixture heated under reflux for 1 hour. Afterthe mixture has cooled to room temperature the resulting yellowprecipitate is removed by filtration. There is obtained 9.10 grams ofmaterial melting at 244-245. Recrystallizing from dimethylformamidemelthanol gives material possessing the same melting point.

Anal. Calcd. for: C l-l ClN O C, 46.74; H, 2.49; Cl, 12.55; N, 9.91Found: C, 46.29; H, 2.55; C1, 12.39; N, 10.10

b. Methyl 6-amino-8-chloro-1,4-dihydro-4-oxoquinaldate Catalyticreduction of methyl 8-chloro-l,4-dihydro- 6-nitro-4-oxoquinaldate by theprocedure described above for methyl 5-amino-8-chloro-1,4-dihydro-4-oxoquinaldate gives 6-amino-8-chloro-l,4-dihydro-4- oxoquinaldate.

c. Product Treatment of methyl 6-amino-8-chloro-1,4-dihydro-4-oxoquinaldate with ethyl oxalyl chloride in the presence oftriethylamine followed by saponification of the resulting diesteraccording to the general procedure described above for(2-carboxy-l,4-dihydro-8-methyl-4- oxo-7-quinolyl)oxamic acid gives(2-carboxy-8-chlorol,4-dihydro-4-oxo-6-quinolyl)oxamic acid.

The compositions of the present invention are presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, sterile parenteralsolutions or suspensions, eye drops and oral solutions or suspensions,and oil-inwater and water-in-oil emulsions containing suitablequantities of the compound of Formula la. The preferred method ofadministration is by inhalation into the lung by means of an aerosolliquid or powder for insufflation.

For oral administration either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof formula la is mixed with conventional ingredients such as talc,magnesium stearate, dicalcium phosphate, magnesium aluminum silicate,calcium sulfate, starch, lactose, acacia, methylcellulose, andfunctionally similar materials as pharmaceutical diluents or carriers.Capsules are prepared by mixing the compound with an inertpharmaceutical diluent and filling the mixture into a hard gelatincapsule of appropriate size. Soft gelatin capsules are prepared bymachine encapsulation of a slurry of the compound with an acceptablevegetable oil, light liquid petrolatum or other inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs,and suspensions can be prepared. The water-soluble forms can bedissolved in an aqueous vehicle together with sugar, aromatic flavoringagents and preservatives to form a syrup. An elixir is prepared by usinga hydro-alcoholic (ethanol) vehicle witu suitable sweeteners such assugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid of asuspending agent sush as acacia, tragacanth, methylcellulose and thelike.

for parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilizedbefore filling into a suitable vial or ampul and sealing.Advantageously, adjuvants such as a local anesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection issupplied to reconstitute the liquid prior to use. Parenteral suspensionsare prepared in substantially the same manner except that the compoundis suspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The compound can be sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Additionally, a rectal suppository can be employed to deliver the activecompound. This dosage form is of particular interest where the manualcannot be treated conveniently by means of other dosage forms, such asorally or insufflation, as in the case of young children or debilitatedpersons The active compound can be incorporated into any of the knownsuppository bases by methods known in the art. Examples of such basesinclude cocoa butter, polyethylene glycols (Carbowaxes), polyethylenesorbitan monostearate, and mixtures of these with other compatiblematerials to modify the melting point or dissolution rate. These rectalsuppositories can weigh from about 1 to 2.5 grams.

The preferred compositions are those adapted for inhalation into thelung and containing a compound of the invention which is water-soluble.For treatment of allergic conditions of the nose, such as rhinitis,compositions adapted for contact with nasal linings are preferred.

Compositions for inhalation are of three basic types: (1) a powdermixture preferably micropulverized; (2) an aqueous solution to besprayed with a nebulizer; and (3) an aerosol with volatile propellant ina presurized container.

The powders are quite simply prepared by mixing a compound of theformula with a solid base which is compatible with lung tissue,preferably lactose. The powders are packaged in a device adapted to emita measured amount of powder when inhaled through the mouth.

Aqueous solutions are prepared by dissolving the compound of the formulala in water and adding salt to provide an isotonic solution andbuffering to a pH compatible with inhalation. The solutions aredispersed in a spray device or nebulizer and sprayed into the mouthwhile inhaling.

Aerosols are prepared by dissolving a compound of the Formula la inwater or ethanol and mixing with a volatile propellant and placing in apressurized container having a metering valve to release a predeterminedamount of material.

the liquefied propellant employed is one which has a boiling point below65F. at atmospheric pressure. For use in compositions intended toproduce aerosols for medicinal use, the liquified propellant should benontoxic. Among the suitable liquefied propellants which may be employedare the lower alkanes containing up to 5 carbon atoms, such as butaneand pentane, or a lower alkyl chloride, such as methyl, ethyl, or propylchlorides. Further suitable liquefied propellants are the fluorinatedand fluorochlorinated lower alkanes such as are sold under thetrademarks Freon and Genetron. Mixtures of the above-mentionedpropellants may suitably be employed. Examples of these propellants aredichlorodifluoromethane (Freon 12), dichlorotetrafluoroethane (Freon115), trichloromonofluoromethane (Freon ll), dichloromonofluoromethane(Freon 21), monochlorofidluoromethane (Freon 22),trichlorotrifluoroethane (Freon l 13), difluoroethane (Genetron 142-A)and monochlorotrifluoromethane (Freon 13).

The term unit dosage form, as used in the specification and claims,refers to physically discrete units suitable as unitary dosages forhuman subjects and animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticaldiluent, carrier or vehicle. The specifications for the novel unitdosage forms of this invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulareffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for use in humans and animals, asdisclosed in detail in this specification, these being features of thepresent invention. Examples of suitable unit dosage forms in accord withthis invention are tablets, capsules, pills, suppositories, powderpackets, wafers, granules, cachets, teaspoonfuls, tablespoonfuls,dropperfuls, ampuls, vials, aerosols with metered discharges, segregatedmultiples of any of the foregoing, and other forms as herein described.

An effective but non-toxic quantity of the compound is employed intreatment. The dosage of the compound for treatment depends on the routeof administration and the potency of the particular compound. A dosageschedule of from about 0.2 to about 200 mg. of compound in a single doseadministered parenterally or by inhalation in the composition of thisinvention are effective for preventing allergy attacks. Morespecifically, the single dose is from about 1.0 to about 20 mg. ofcompound. The oral and rectal dose is from about 2 to about 400 mg. in asingle dose. More specifically, the single dose is from about 2 to aboutmg. of compound. The dosage to be administered can be repeated up tofour times daily. However, when it is necessary to repeat treatment, apreferred dosage schedule reduces the secondary treatment dosage to fromabout 0.5 percent to about 20 percent of the above dosages, morespecifically, from about 1 to about 10 percent of the above dosages. Inthis manner, a state of allergy prophylaxis can be maintained. Thereduced dosage is taken until that dosage no longer provides effectiveprotection. At that time, the larger dosage is repeated, followed by thereduced dosage. An example of such dosage schedule is the following: Anasthmatic individual insufflates 1.0 mg. of the tris-(hydroxymethyl-)aminomethane salt of 2-carboxy-8-chloro-l,4-dihydro-4-oxo-5-quinolyloxamic acid. Four hours later the individualinsufflates 0.01 mg. of the same compound and every 4 to 6 hoursthereafter insufflates 0.01 mg. of the same compound until effectiveasthma prophylaxis is provided. The individual then insufflates 1.0 mg.of the same compound, then reduces the insufflation dosage to 0.01 mg. 4to 6 hours later. The dosage schedule continues in this manner.

The administration of the composition of the present invention to humansand animals provides a method for the prophylactic treatment of allergyor all anaphylactic reactions of a reagin or a non-reagin mediatednature. That is to say, these compositions, when administered to asensitized individual prior to the time that the individual comes intocontact with substances (antigens) to which he is allergic, will preventthe allergic reaction which would otherwise occur.

For example, the process can be used for prophylactic treatment of suchchronic conditions as bronchial asthma, allergic rhinitis, food allergy,hay fever, urticaria, auto-immune diseases, exercise induced asthma,stress induced asthma, and bird fanciers disease.

(2Carboxy-l ,4-dihydro-8-methyl- 4-oxo-4-quinolyl)oxamic acid 200 Gm.Dicalcium phosphate 1,000 Gm. Methylcellulose, U.S.P. (l5 cps) 60 Gm.Talc Gm. Corn starch 200 Gm. Calcium stearate l2 Grn.

The compound and dicalcium phosphate are mixed well, granulates with 7.5percent solution of methylcellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the talc, starch and magnesiumstearate, and compressed into tablets.

These tablets are useful in preventing hay fever attacks at a dose of 1tablet every 4 to 6 hours.

EXAMPLE 8 One thousand two-piece hard gelatin capsules, each containing20 mg. of(2-carboxy-l,4-dihydro-8-methyl- 4-oxo-5-quinolyl)oxamic acidare prepared from the following types and amounts of ingredients:

4-oxo-5-quinolyl)oxamic acid 20 Gm. Talc 150 Grn. Magnesium stearate 1Gm.

The ingredients are mixed well and filled into capsules of the propersize.

Capsules so prepared are useful in preventing attacks of bronchialasthma at a dose of one capsule every 4 to 6 hours.

EXAMPLE 9 One thousand tablets, each containing 20 mg. of (2- carboxy-l,4-dihydro-8-methyl-4-oxo-5- quinolyl)oxamic acid are prepared from thefollowing types and amounts of ingredients:

(2-Carboxyl ,4-dihydro-8-methyl- 4-oxo-5-quinolyl)oxamic acid 20 Gm.Microcrystalline cellulose NF 420 Gm. Starch 100 Gm. Magnesium stearatepowder Gm.

The ingredients are screened and blended together and pressed into 545mg. tablets.

The tablets are useful to protect against food allergy at a dose of 1tablet before meals.

EXAMPLE 10 A sterile preparation suitable for intramuscular injectionand containing 2 mg. of (2-carboxy-l ,4dihydro-8-methyl-4-oxo-7-quinolyl)oxamic acid in each milliliter is prepared fromthe following ingredients:

(Z-Carboxyl ,4 dihydro-8-methyl- 4-oxo-7-quinolyl)oxamic acid 2 Gm.Benzyl benzoate 200 ml. Methylparaben 1.5 Gm. Propylparaben 0.5 Gm.Cottonseed oil q.s. 1,000 ml.

One milliliter of this sterile preparation is injected for prophylactictreatment of allergic rhinitis.

EXAMPLE 1 1 Six hundred ml. of an aqueous solution containing 2.0 mg. ofthe tris(hydroxymethyl)aminomethane (THAM) salt of(2-carboxy-8-chloro-1,4-dihydro-4- oxo-5-quinolyl)oxamic acid per ml. isprepared as follows:

I Tris(hydroxymethyl)aminomethane salt of (2-carboxy-8- chlorol,4-dihydro-4-oxo-5- quinolyl)oxamic acid 1.2 Gm. Sodium chloride 5 Gm.Water for injection q.s. 600 ml.

The THAM salt and sodium chloride are dissolved in sufficient water tomake 600 ml. and sterile filtered.

The solution is placed in nebulizers designed to deliver 0.25 ml. ofsolution per spray.

The solution is inhaled into the lungs every 4 to 6 hours for preventionof asthmatic attacks.

EXAMPLE 12 EXAMPLE l3 Twelve grams of an aerosol composition areprepared from the following ingredients:

Tris(hydroxymethyl )aminomethanesalt of (Z-carboxy-8-chlorol ,4-dihydro-4-oxo-5-quinolyl )oxamic acid .50 Gm. Freon 12 L440 Gm. Freon114 2.160 Gm. Water 7.300 Gm. Sorbitan monoleate 0.600 Gm.

The THAM salt is dissolved in the water and combined with the otherconstituents under pressure. The 12 grams of composition are added to a13 cc. plastic coated bottle and capped with a metering valve. Themetering valve releases 80 mg. of composition in an aerosol. The aerosolis inhaled every 4 to 6 hours for prevention of asthmatic attacks.

EXAMPLE 14 In individuals who require continual treatment in theExamples 7 through 13, the dosage of the Example is given initially andeach succeeding administration of the drug is at 1/50 of the initialdosage. This maintenance dosing is continued until effective allergyprophylaxis is not obtained. The initial dosage of Examples 7 through 13is then started once more, followed by the maintenance dosages.

EXAMPLE 15 After allowing for the differing solubilities of thecompounds and the activity of the particular compound as measured, forexample, by the in vivo rat passive cutaneous anaphylaxis assay, asuitable quantity of each of the compounds of Table II and Table III aresubstituted for the active compound in the compositions and uses ofExamples 7 through 14. Results showing anti-allergy activity areobtained.

EXAMPLE 16 The rat passive cutaneous anaphylaxis assay is run in thefollowing manner:

Female Sprague-Dawley 250 gm. rats are skinsen'sitized with ratani-ovalbumin homocycotropic antibody that is heat labile and has apassive cutaneous anaphylaxis titer of 1:128. After a 72-hour latencyperiod, the animals are challenged i.v. with 4 mg. ovalbumin (OA) 5 mg.Evans blue dye and the test compound. Thirty minutes later theextravascular bluing that results from antigen antibody combination atthe skin side is read. Antibody dilutions are used such that in controlanimals a 4 mm spot is the lowest detectable spot, and 4 or 5 lowerdilutions are used to give a range of antibody in each animal. Four tofive animals are used for each variable in the experiment. Percentinhibition of the PCA assay is calculated by comparing the spot scoresof treated rats with the spot scores of control rats. The spot score isthe total number of detectable spots over the number of animals.

The tris (hydroxymethyl)aminomethane salt of (2- carboxy-8-chlorol,4-dihydro-4-oxo-5- quinolyl)oxamic acid is prepared by dissolving thecarboxylic acid in an equivalent weight of aqueoustris(hydroxymethyl)-aminomethane and is treated in the rat passivecutaneous anaphylaxis assay in the above manner.

The inhibitory dose for the tris(hydroxymethyl)- aminomethane salt of(2-carboxy-8-chloro-1,4- dihydro-4-oxo-5-quinolyl)oxamic acid, whengiven i.v., is 0.10 mg./kg.

I claim:

1. A compound of the formula wherein M is selected from the groupconsisting of hydrogen and a non-toxic pharmaceutically acceptablecation;

X is selected from the group consisting of hydrogen, alkyl from one tothree carbon atoms, inclusive; alkoxy from one to three carbon atoms,inclusive halogen, and trifluoromethyl with the proviso that when X ishydrogen, the

grouping is limited to the 6 position.

2. A compound in accordance with claim 1 wherein M is an amine cation, Xis selected from the group consisting of alkyl from one to three carbonatoms. inclusive, and halogen; and

is at the 7 position.

3. A compound in accordance with claim 2 wherein M istris(hydroxymethyl)methylammonium.

4. (Z-Carboxy-l ,4-dihydro-8-methyl-4-oxo-7- quinolyl)oxamic acidaccording to claim 1.

5. (2-Carboxy-l,4-dihydro-4-oxo-6-quinolyl)oxamic acid according toclaim 1.

quinolyl)oxamic acid according to claim 1.

10. A compound in accordance with claim 3 wherein X is methyl.

1. A COMPOUND OF THE FORMULA
 2. A compound in accordance with claim 1wherein M is an amine cation, X is selected from the group consisting ofalkyl from one to three carbon atoms, inclusive, and halogen; and
 3. Acompound in accordance with claim 2 wherein M istris(hydroxymethyl)methylammonium. 4.(2-Carboxy-1,4-dihydro-8-methyl-4-oxo-7-quinolyl)oxamic acid accordingto claim
 1. 5. (2-Carboxy-1,4-dihydro-4-oxo-6-quinolyl)oxamic acidaccording to claim
 1. 6.(2-Carboxy-1,4-dihydro-8-methyl-4-oxo-5-quinolyl)oxamic acid accordingto claim
 1. 7. (2-Carboxy-1,4-dihydro-8-methyl-4-oxo-6-quinolyl)oxamicacid according to claim
 1. 8.(2-Carboxy-8-chloro-1,4-dihydro-4-oxo-5-quinoly)oxamic acid according toclaim
 1. 9. (2-Carboxy-8-chloro-1,4-dihydro-4-oxo-6-quinolyl)oxamic acidaccording to claim
 1. 10. A compound in accordance with claim 3 whereinX is methyl.